1. Field of the Invention
The present invention relates to erythromycin A derivatives and the method for the preparation of the same.
2. Description of the Prior Art
6-O-Methylerythromycins are useful as anti-bacterial agents or intermediates for synthesis of the antibacterial agents. For example, 6-O-methylerythromycin A is not only stable under the acidic conditions but also has a strong antibacterial activity when compared with erythromycin A. Especially, this compound shows an excellent effect for treatment of infections by oral administration, and therefore it is a useful antibacterial agent.
There are known in the past some methods for methylating the hydroxy group at the 6-position of the erythromycin A derivatives, for example, (1) a method which comprises substituting the hydrogen atom of the hydroxy group at the 2xe2x80x2-position and the methyl group of the dimethylamino group at the 3xe2x80x2-position of the erythromycin A derivatives by benzyloxycarbonyl groups, and then methylating the resulting compound (U.S. Pat. No. 4,331,803), and (2) a method which comprises converting erythromycin A derivatives having the protected hydroxy group at the 2xe2x80x2-position and/or the protected dimethylamino group at the 3xe2x80x2-position into the various kind of the substituted oxime derivative, and then methylating the substituted derivatives (European Patent 158,467).
However, since erythromycin A has many hydroxy groups, there are obtained various kind of erythromycin A derivatives which are methylated at hydroxy groups at any other than the 6-position as the by-products by the method of item (1). Accordingly, this method requires the complicated procedure for purification of the 6-O-methylerythromycin A derivatives, and has drawback of causing low yield of said derivatives. Although it is possible to methylate selectively the 6-hydroxy group by the method of item (2), when the erythromycin A 9-oxime derivative whose 2xe2x80x2-hydroxy group only is protected is methylated, the 3xe2x80x2-dimethylamino group is changed to a methyl quaternary salt under ordinary methylation conditions. Furthermore it is difficult to return the salt to a dimethylamino group, accordingly, it is necessary to protect both of the 2xe2x80x2-hydroxy group and 3xe2x80x2-dimethylamino group for the practical preparation method.
As a result of the various researches to solve the drawbacks of the above known methods, the present inventors have found the fact that erythromycin A derivative whose 2xe2x80x2-hydroxy group is protected with the substituted silyl groups is not quaternarized at the adjacent 3xe2x80x2-dimethylamino group even under ordinary methylation conditions, and the present invention has been completed.
An object of the present invention is to provide 6-O-methylerythromycin A derivatives represented by the general formula 
wherein R1 is a 2-alkenyl group having 3 to 15 carbon atoms, an arylmethyl group, or an arylmethyl group substituted by 1 to 3 of a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a nitro group or an alkoxycarbonyl group having 2 to 6 carbon atoms, R2 is a substituted silyl group of formula xe2x80x94SiR4R5R6 (wherein R4, R5 and R6 are the same or different, and each is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a phenyl substituted alkyl group in which the alkyl moiety has 1 to 3 carbon atoms, a phenyl group, a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms, with the proviso that at least one of R4, R5 and R6 is other than hydrogen atom) and R3 is a hydrogen atom or R2.
Another object of the present invention is to provide erythromycin A derivatives represented by the general formula 
wherein R1, R2 and R3 are as defined above.
Still another object of the present invention is to provide a method for preparing 6-O-methylerythromycin A derivatives of formula I which comprises reacting, in any desired sequence, erythromycin A 9-oxime with a compound of formula R1xe2x80x94X (wherein R1 is as defined above, and X is a halogen atom) and with a substituted silylating agent having R2 group to give a compound of formula II, and then reacting the compound of formula II with a methylating agent.
In the present invention, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkenylxe2x80x9d used alone or as combined with the other group mean those whose carbon chain may be linear or branched. The term xe2x80x9carylmethyl groupxe2x80x9d means a benzyl group, a benzhydryl group, a trityl group or a naphthylmethyl group. Examples of the substituted arylmethyl group are a p-methoxybenzyl group, a p-chlorobenzyl group, a m-chlorobenzyl group, an o-chlorobenzyl group, a 2,4-dichlorobenzyl group, a p-bromobenzyl group, a m-nitrobenzyl group, a p-nitrobenzyl group and the like. Examples of 2-alkenyl group for R1 are an allyl group, a methallyl group, a crotyl group, a prenyl group, a 2-pentenyl group, a 2-ethyl-2-butenyl group, a geranyl group, a neryl group and the like. The term xe2x80x9chalogen atomxe2x80x9d refers to a chlorine, a bromine, an iodine atom and the like. Examples of the substituted silyl group are a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a (triphenylmethyl)dimethylsilyl group, a tert-butyldiphenylsilyl group, a diphenylmethylsilyl group, a diphenylvinylsilyl group, a methyldiisopropylsilyl group, a tribenzylsilyl group, a tri(p-xyryl)silyl group, a triphenylsilyl group, a diphenylsilyl group, a dimethyloctadecylsilyl group and the like.
The present invention is illustrated below in more detail. At first, etherification of erythyromycin A 9-oxime with a compound of formula R1xe2x80x94X is carried out according to the known method per se, for example, the method described in European Patent No. 158,467 to give a compound of formula 
wherein R1 is as defined above.
The reaction of the compound of formula III with the silylating agent is carried out in a solvent in the presence of a base at 0xc2x0 C. to the reflux temperature of the solvent, preferably at room temperature with stirring. Examples of the silylating agent used are chlorosilanes such as trimethylchlorosilane, tert-butyldimethychlorosilane and the like; silylamines such as 1,1,1,3,3,3-hexamethyldisilazane, trimethylsilylimidazole, dimethylaminotrimethylsilane and the like; bis(trimethylsilyl)acetamide, trimethylsilyldiphenylurea, bis(trimethylsilyl)urea and the like. The amount of the silylating agent used is 1 to 10 equivalents, preferably 1 to 5 equivalents relative to the compound of formula III.
Examples of the solvent used in the reaction are acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform and the like. Examples of the base are inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and organic bases such as trimethylamine, triethylamine, pyridine, 1,8-diaza-bicyclo[5,4,0]unde-7-cene, imidazole and the like.
Although difference of the silylation at the 2-position only between both of the 2xe2x80x2- and 4xe2x80x3-positions of the compound of formula III depends on the reaction conditions, it is preferable to use a chlorosilane for the silylation at the 2-position only, and it is preferable to use both a chlorosilane and a silylamine or 1,1,1,3,3,3-hexamethyldisilazane for the silylation at the 2xe2x80x2- and 4xe2x80x3-positions.
Alternatively, the compound of formula II can be obtained by etherification after silylation of erythromycin A 9-oxime. Namely, erythromycin A 9-oxime is reacted with the silylating agent under the same silylation conditions as described above, and then the resulting compound is reacted with the compound of formula R1xe2x80x94X under the same etherification conditions as described above to give the compound of formula II.
The reaction of the compound of formula II with the methylating agent for preparing the compound I can be carried out in a solvent in the presence of a base at xe2x88x9215xc2x0 C. to room temperature, preferably at 0xc2x0 C. to room temperature with stirring. Examples of the methylating agent are methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, methyl methanesulfonate and the like. It is sufficient to use 1-3 molar equivalents of the methylating agent relative to the compound of formula II. Examples of the solvents used are polar aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents and a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate or the like. Examples of the base are sodium hydroxide, potassium hydroxide, sodium hydride, potassium t-butoxide, potassium hydride and the like. The amount of the base used is usually 1-2 molar equivalents relative to the compound of formula II.
In order to prevent the quaternarization of the 3xe2x80x2-dimethylamino group when the compound of formula II is methylated, it is essential to protect the 2xe2x80x2-hydroxy group with the substituted silyl ether, but not necessarily essential to etherify the 4xe2x80x3-hydroxy group with the substituted silyl group.
The compound of formula II may be used after isolation or without isolation for reacting with the methylating agent.
Although erythromycin A 9-oxime derivatives of the present invention exist in two isomers (syn- and anti-forms), for the purpose of the present invention, these compounds may exist in either of the isomers and in a mixture thereof.
In the method for preparing the 6-O-methylerythromycin A derivatives of the present invention, it is not necessary to protect the 3xe2x80x2-dimethylamino group, therefore, it is not necessary to carry out the 3xe2x80x2-N-methylation, either.
The methylation of the hydroxy group at the 6-position of the present invention has good selectivity as well as the prior art method. Furthermore, the substituted silyl groups used for the protection of the hydroxy groups at the 2xe2x80x2- and 4xe2x80x3-positions can be easily eliminated.
Therefore, the present invention can provide 6-O-methylerythromycin A in high yield and economically. Namely, the compound of formula I can be led to 6-O-methylerythromycin A, for example, by the following method.
The elimination of the substituted silyl groups (R2 and R3) at the 2xe2x80x2- and 41-positions of the compound of formula I can be carried out easily by treatment with an acid (e.g., formic acid) in an alcohol or with tetrabutyl ammoniumfluoride in tetrahydrofuran.
The elimination of R1 group of the resulting compound can be carried out by homogeneous or heterogeneous hydrogenolysis known per se. For example, this reaction may be carried out in an alcoholic solvent (e.g., methanol, ethanol and the like) in the presence of a catalyst such as palladium black or palladium carbon under a hydrogen atomosphere with stirring. The addition of formic acid, acetic acid or the like is convenient for the progress of the reaction.
This reaction can also be carried out easily in the presence of a suitable hydrogen source (e.g., ammonium formate, sodium formate, and a mixture of these formates and formic acid) and a catalyst (e.g., palladium carbon, palladium black and the like) in an organic solvent (e.g., methanol, ethanol, N,N-dimethylformamide and the like) with stirring at room temperature to 70xc2x0 C.
Furthermore, this reaction may be carried out by using a platinum group compound and a ligand as a catalyst. Examples of the platinum group compound are the salts or complexes of ruthenium, rhodium, palladium and platinum, and examples of the ligand are phosphor compounds such as triphenylphosphine, tri-n-butylphosphine, triethylphosphite, 1,2-ethylene(diphenyl)phosphine and the like. Usually, mixture of palladium acetate and triphenylphosphine may be used. This reaction can be carried out in the presence of formic acid or a salt thereof. Examples of the salt of formic acid are ammonium salts thereof such as ammonium formate, trimethylammonium formate, triethylammonium formate and the like, and alkali metal salts thereof such as sodium formate, potassium formate and the like.
The elimination procedure of R2 and R3 and that of R1 may be carried out in the reverse order without any trouble.
6-O-Methylerythromycin A 9-oxime thus obtained can be converted easily to 6-O-methylerythromycin A by deoximation using sodium hydrogen sulfite, titanium trichloride-ammonium acetate, sodium nitrite-hydrochloric acid, sodium hydrosulfite (Na2S2O4) and the like.
Next, the present invention will be concretely illustrated by Examples which show the method for preparing the compound of formula I and Referential Examples which show the method for preparing 6-O-methylerythromycin A.